Abstract
Overexpression of ATP-binding cassette transporter superfamily G member 2 (ABCG2), is known as a major mechanism mediating multidrug resistance (MDR) in cancer cells. MLN7243 is a small-molecule ubiquitin activating enzyme inhibitor currently under clinical investigation. The aim of the current study is to determine if MLN7243 is a substrate of MDR-related ABCG2 transporter. Our results showed that cancer cells overexpressing ABCG2 transporter were resistant to MLN7243 compared to the parental cells, while knockout of ABCG2 gene or pharmacological inhibition of ABCG2 efflux function completely reversed the drug resistance. Unexpectedly, the endogenous low expression of ABCG2 is sufficient to confer cancer cells resistance to MLN7243. The ABCG2 ATPase assay and HPLC assay suggested that MLN7243 can significantly stimulate ABCG2 ATPase activity and be pumped out from ABCG2-overexpressing cells by ABCG2. The docking analysis also implied that MLN7243 binds to ABCG2 drug-binding pocket with optimal binding affinity. However, MLN7243 did not competitively inhibit the efflux of other ABCG2 substrate drugs, indicating it may not serve as an MDR reversal agent. In conclusion, our study provides direct in vitro evidence to show that MLN7243 is a potent ABCG2 substrate. If our results can be translated to humans, it suggests that combining MLN7243 with ABCG2 inhibitors may enhance the anticancer efficacy for patients with high tumor ABCG2 level.
Highlights
Multidrug resistance (MDR) is one of the major challenges in cancer therapy
Our results showed that all ABCG2overexpressing cells were significantly less sensitive to MLN7243 than the parental cells, as indicated by the gap between the cell viability curves
The results suggest that ATP-binding cassette transporter superfamily G member 2 (ABCG2) inhibition is able to enhance the sensitivity of drug-resistant cells to MLN7243
Summary
Multidrug resistance (MDR) is one of the major challenges in cancer therapy. The definition of MDR in cancer is the insensitivity of cancer cells to the neoplastic drugs (which has distinct chemical structures and mechanisms of action) despite earlier sensitivity to them. During exposure to anticancer drugs, cancer cells may develop MDR through decreasing drug uptake by downregulation of some membrane carriers or receptors, increasing drug efflux by upregulation of membrane transporters, and increasing the mutation of genes (Toyoda et al, 2019). ABCG2 transporter can mediate the efflux of a broad range of anticancer drugs and render cancer cells resistance to these drugs (Yang et al, 2020). Palshof et al (2020) found that colorectal cancer patients with low ABCG2 expression level had a higher chance of obtaining objective response when receiving irinotecan-based treatment. Identifying anticancer drugs that are ABCG2 substrates can be beneficial to the development of clinical treatment strategy and to monitor the occurrence of drug resistance
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